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ORIGINAL ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 4  |  Page : 204-210

Correlation between serum surfactant protein-D level with respiratory compliance and acute respiratory distress syndrome in critically ill COVID-19 Patients: A retrospective observational study


1 Department of Anesthesiology and Reanimation, Faculty of Medicine, Dr. Soetomo General Hospital, Airlangga University, Surabaya, Indonesia
2 Department of Public Health and Preventive Medicine, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

Date of Submission04-Apr-2022
Date of Acceptance20-Jul-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Dr. Jayadi
Department of Anesthesiology and Reanimation, Faculty of Medicine, Dr. Soetomo General Hospital, Airlangga University, Surabaya
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijciis.ijciis_27_22

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   Abstract 


Background: Acute respiratory distress syndrome (ARDS) is one of the manifestations of severe coronavirus disease 2019 (COVID-19) with low respiratory compliance and poor oxygenation as main characteristics and mortality rate of 50%–94%. Surfactants, including surfactant protein D (SP-D), have a role in maintaining respiratory compliance. This study aimed to analyze the relationship between serum SP-D levels with respiratory compliance and ARDS in patients with critically ill COVID-19 pneumonia.
Methods: This study was a cross-sectional study. Subjects were adult reverse transcription–polymerase chain reaction-confirmed COVID-19 patients who had ARDS treated with invasive mechanical ventilation. All data were obtained from medical records. Statistical analysis was done using Spearman test, Mann–Whitney test, and receiver operating characteristic curve.
Results: Serum level of SP-D was significantly correlated with static respiratory compliance (P = 0.009; correlation coefficient [rs] = 0.467). Serum SP-D levels correlated with ARDS severity (P < 0.001). SP-D levels had a very strong diagnostic value for ARDS severity, with an optimal cutoff value of 44.24 ng/mL (sensitivity 92.3%; specificity 94.1%). ARDS severity also correlated significantly with respiratory compliance (P = 0.005; correlation coefficient 0.496).
Conclusion: Higher serum SP-D levels were associated with lower respiratory compliance, ARDS severity, and may be utilized diagnostically to identify patients with severe ARDS.

Keywords: Coronavirus disease 2019, critical care, lung compliance, pulmonary surfactant-associated protein d, respiratory distress syndrome


How to cite this article:
Jayadi, Airlangga PS, Kusuma E, Waloejo CS, Salinding A, Lestari P. Correlation between serum surfactant protein-D level with respiratory compliance and acute respiratory distress syndrome in critically ill COVID-19 Patients: A retrospective observational study. Int J Crit Illn Inj Sci 2022;12:204-10

How to cite this URL:
Jayadi, Airlangga PS, Kusuma E, Waloejo CS, Salinding A, Lestari P. Correlation between serum surfactant protein-D level with respiratory compliance and acute respiratory distress syndrome in critically ill COVID-19 Patients: A retrospective observational study. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Feb 9];12:204-10. Available from: https://www.ijciis.org/text.asp?2022/12/4/204/364737




   Introduction Top


Many coronavirus disease 2019 (COVID-19) infections cause severe symptoms, with rates of acute respiratory distress syndrome (ARDS) as high as 67%.[1] COVID-19-associated ARDS (CARDS) carries an associated mortality rate of 65.7%–94%.[2] According to the Berlin Criteria, ARDS is defined as acute hypoxemic respiratory failure of any cause with the appearance of bilateral infiltrates on computed tomography scan or chest X-ray, with no cardiogenic or hydrostatic causes.[1] The main characteristics of ARDS are poor oxygenation and reduced pulmonary compliance. ARDS is a result of acute and diffuse inflammatory processes, resulting in increased respiratory vascular permeability, increased respiratory resistance, loss of air-filled lung tissue, increased shunting, increased death physiological space, and reduced respiratory compliance.[3]

The prominent clinical presentation of ARDS is decreased static respiratory compliance (Cstat). Respiratory compliance is defined as volume change that occurs per unit pressure change in the respiratory system.[4] Elastin and collagen fibers of the lungs form elastic properties; thus, the lungs will tend to deflate and stiffen. The decrease in respiratory compliance in ARDS is not caused by stiff tissue, but by the hydrostatic pressure of the interstitial edema which compresses the alveoli to collapse.[5] In lungs with ARDS, the alveoli tend to collapse due to the accumulation of inflammatory cells and fluid in the interstitial spaces of the alveoli, as well as reduced surfactant function.[5]

It has previously been reported that among hospitalized CARDS patients, 34.6% had very low respiratory compliance, 63.2% had low-normal compliance, while only 2.2% had high compliance.[1] Patients with very low respiratory compliance tend to be less responsive to mechanical ventilation and have a poor prognosis.[1]

Surfactants play a role in maintaining respiratory compliance by reducing the surface tension of the alveoli so that lung collapse at the end of expiration can be prevented. In addition, surfactants also function in interacting and killing pathogens or preventing their spread and modulating immune responses.[6] The surfactants are predominantly composed of phospholipids and the remainder by surfactant proteins (SP) A, B, C, and D.[7] SP-D is a member of the collectin family mainly produced by Type II alveolar cells. Respiratory collectins are normally expressed exclusively in the lungs and only leak into the circulation in response to increased respiratory vascular permeability due to loss of structural and functional integrity.[8] This condition is accurately reflected in COVID-19 pneumonia. Higher serum SP-D levels were found in severe cases of COVID-19, especially in the acute phase.[9],[10]

There have been many studies on SP-D levels as a potential prognostic marker in the severity of COVID-19, but studies on the association of SP-D with respiratory compliance are rare, especially in human subjects. Thus, this study aimed to analyze the relationship between serum SP-D levels with respiratory compliance and ARDS in critically ill patients with COVID-19 pneumonia.


   Methods Top


This study was a retrospective observational analytical study with cross-sectional design. The study was approved by local ethical committee. The manuscript adheres to the STROBE guideline. Subjects were reverse transcription–polymerase chain reaction (RT-PCR) confirmed COVID-19 patients who were admitted to a special isolation ward during June 1–August 31, 2020. Inclusion criteria were patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via RT-PCR, age ≥18 years, were diagnosed with ARDS according to the Berlin criteria, treated with invasive mechanical ventilation, and had data of SP-D, arterial blood gas analysis, and Cstat at the same time. Exclusion criteria included history of chronic lung disease, immune related disease, or incomplete data. Classification of ARDS severity was based on the Berlin definition where a ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio) <100 was classified as severe ARDS, 100–200 as moderate ARDS, 201–300 as mild ARDS, and >300 categorized as no ARDS.

Serum samples for measuring SP-D levels and arterial blood samples for blood gas analysis were collected only one time at the same time as ARDS diagnosed. Serum SP-D level was measured using Elabscience® human SP Elisa kit (Elabscience Biotechnology Inc., Houston, United States). Ventilators used were Hamilton-C2 ventilator (Hamilton Medical AG, Bonaduz, Switzerland) with pressure control ventilation setting. Respiratory compliance was measured by the ventilator machines. Recording of Cstat values shown on the monitors was done by anesthesiologists, Cstat <20 ml/cmH2O, 20–49 ml/cmH2O, 50–60 ml/cmH2O, and >60 ml/cmH2O were considered as very low, low, normal, and high respiratory compliance, respectively.

Statistical analysis

Data of all patients who met the inclusion and exclusion criteria were obtained from their medical records. Descriptive data were expressed as mean, median, numbers, and percentages. The data collected were analyzed using Spearman test and receiver operating characteristic (ROC) curve. Spearman test was used to analyze the significance of the relationship between serum level of SP-D and level of respiratory compliance, between level of respiratory compliance and severity of ARDS, also correlation between serum level of SP-D and severity of ARDS. ROC curve was used to analyze the diagnostic value of SP-D levels for severity of ARDS. The results were considered significant when P < 0.05.


   Results Top


Eighty-eight potential patients were identified, of which 58 were excluded, and 30 were included in the final analysis. The median age was 51.50-year-old and 70% of them were male [Table 1]. Comorbidities were found in 70% of patients, three of the most common comorbidities were hypertension, diabetes mellitus, and geriatric [Figure 1].
Figure 1: Subjects' comorbidities

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Table 1: Subjects' characteristics

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The median of serum SP-D level was 36.745 ng/mL (range 8.03–100.81 ng/mL). The mean ± standard deviation (SD) of SP-D level was 46.875 ± 33.752 ng/mL. The mean value and SD were considered almost the same and the wide range indicated that the results of the SP-D serum levels were highly varied. In this study, no patient had high respiratory compliance. Most of them had low respiratory compliance and only 10% of them had normal respiratory compliance. Data of severity of ARDS showed that no patient had mild ARDS and majority of them had moderate ARDS. Mean value and SD of P/F ratio was 117.585 ± 40.880 which was considered as moderate ARDS according to the Berlin's criteria.

Statistical analysis using Spearman test showed a significant correlation with moderate strength between serum level of SP-D and respiratory compliance (P = 0.009; correlation coefficient [rs] = 0.467). The mean value of serum SP-D for each category of respiratory compliance described in [Figure 2].
Figure 2: Mean value of serum SP-D. SP-D: Surfactant protein D

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The mean value of serum SP-D level in patients with moderate and severe ARDS was 21.76 ng/mL and 79.71 ng/mL, respectively [Figure 3]. Spearman test was done to analyze correlation between serum level of SP-D and severity of ARDS. Serum SP-D levels correlated with ARDS severity (P < 0.001). Analysis using ROC curve was done to determine the strength of the diagnostic value by obtaining the area under the curve value and the optimal cutoff value between SP-D serum levels and ARDS. The results of the ROC curve analysis showed that the area under the curve of SP-D levels in the serum of ARDS patients was 0.973 (95% confidence interval [CI] 0.922–1.000). This meant that SP-D levels had a very strong diagnostic value for ARDS severity, with an optimal cutoff value of 44.24 ng/mL (sensitivity 92.3%; specificity 94.1%) [Figure 4] & [Figure 5].
Figure 3: Boxplot diagram of distribution of SP-D Serum Levels based on the Severity of ARDS. SP-D: Surfactant protein D, ARDS: Acute respiratory distress syndrome

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Figure 4: ROC curve of serum level of SP-D and ARDS. SP-D: Surfactant protein D, ARDS: Acute respiratory distress syndrome, ROC: Receiver operating characteristic

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Figure 5: Optimal cutoff of sensitivity and specificity between SP-D serum levels and severity of ARDS. SP-D: Surfactant protein D, ARDS: Acute respiratory distress syndrome

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In patients with moderate ARDS, most of them had low respiratory compliance. On the other hand in patients with severe ARDS, 7 of them had very low respiratory compliance, while 6 of them had low respiratory compliance [Figure 6]. Correlation between severity of ARDS and respiratory compliance was analyzed using Spearman test. ARDS severity and respiratory compliance correlated with moderate strength (r2 = 0.496, P = 0.005) [Figure 7].
Figure 6: Proportion of pulmonary compliance level in ARDS patients. ARDS: Acute respiratory distress syndrome

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Figure 7: Regression plot of association between Crs and P/F Ratio

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   Discussion Top


Based on the role of SP-D in lung protection, inflammatory response regulation, and its dysregulation in lung disease, it is hypothesized that increased levels of SP-D in blood serum may be caused by respiratory tissue damage.[11] In the 2020 study by Kerget et al., 88 COVID-19 patients were examined for SP-D on day 0 and day 5 since hospital admission. This study compared the value of SP-D levels in COVID-19 patients with or without ARDS and the control group. The mean SP-D level in the control group was 21.1 ng/mL, while the average SP-D on day 0 of the ARDS group was 83.3 ng/mL and 46.5 ng/mL for the non-ARDS group. Measurement of SP-D levels was again carried out on day 5, where the ARDS group got 46.4 ng/mL and the non-ARDS group got 22.4 ng/mL. This results showed that in patients with COVID-19, SP-D levels were higher in patients with ARDS than in those without ARDS (P = 0.001). Likewise, the SP-D measurements in the nonsurvivors versus survivors group (96.7 ± 37.2 ng/ml vs. 56.9 ± 43.5 ng/ml, P = 0.03).[12]

A study by Saito et al. examined SP-D levels in 46 COVID-19 patients. Saito et al. divided into groups of severe and mild cases and then observed SP-D levels on days 3, 6 and 8. The results showed that the SP-D levels in cases of mild to severe disease had a significant difference (61.9 ± 50.7 vs. 237 ± 210, P < 0.001). In addition, this study also stated that in the severe disease group, the increase in SP-D values on day 8 when compared to day 3 was 8.5 times higher where the increase in SP-D levels was also accompanied by worsening clinical condition.[9]

In this study, the overall mean serum SP-D level was 46.87 ng/mL with a SD of 33.752 ng/mL. This value was higher than normal serum SP-D levels in the control population which showed a mean of 31.0 ± 12.4 ng/ml.[13] This value of SP-D serum level is lower when compared to the mean value of SP-D in the case of influenza H1N1 (434.5 ng/mL) conducted by Delgado et al. This may be caused by the pathophysiological process of COVID-19 itself, where as it is known that SARS CoV-2 enters the respiratory tract and binds to the angiotensin converting enzyme-2 receptor to enter Type II alveolar cells. Type II alveolar cells produce surfactant, so damage to these cells early in the course of the disease can cause a decrease in the amount of respiratory surfactant. This causes the lower number of SP-Ds that leak into the systemic circulation because the number of SP-Ds in the lungs from the beginning has already decreased.[11] A study by Arroyo and Kingma reported that COVID-19 patients exhibited decreased respiratory SP-D concentrations (median = 68.9 ng/mL) compared to levels reported in the literature for healthy subjects, which ranged from 900 to 1300 ng/mL.[14]

Gu et al. reported that the mean P/F ratio in COVID-19 patients admitted to the intensive care unit (ICU) was 172.98 ± 119.38 mmHg.[15] Roozeman et al. reported that COVID-19 patients who were admitted to the ICU and received invasive mechanical ventilation had mean P/F ratio of 124 ± 45 for survived patients and 120 ± 44 for deceased patients.[16] P/F ratio of COVID-19 patients provides information about the clinical course to determine the severity of ARDS. The lungs are the main organs that are attacked by the SARS-CoV2 virus, its infection causes hypoxia and respiratory distress. Postmortem analysis revealed inflammatory cell infiltration into hyaline membranes, alveoli and perivascular areas.[15] In this study, the median P/F ratio was 114.5 mmHg and the mean was 117.56 ± 40.88 mmHg.

Boscolo et al. reported that COVID-19 patients from 25 ICUs in Italy had a median respiratory compliance value of 48 ml/cmH2O with an interquartile value of 39–60 ml/cmH2O.[17] Studies conducted in France and Belgium stated that among COVID-19 patients admitted to the ICU, the mean respiratory compliance value was 37.6 ± 13 mL/cmH2O. The value of Cstat was measured on the 1st day of hospitalization, and the value continued to decrease from the 1st day to the 14th day of treatment. According to a study by Vandenbunder et al., a decrease in the value of Cstat is not associated with patients' clinical condition.[18]

Respiratory compliance is usually used to measure the extent to which the lungs will expand (change in lung volume) which depends on the elasticity of the lung tissue, surface tension of elastic forces, surfactant, lung volume, and age.[19] One of the diseases with impaired compliance is chronic obstructive respiratory disease (COPD) where there is destruction of lung tissues so that respiratory compliance increases causing the lungs to be in a state of hyperinflation.[20] Several studies have studied the association between SP-D and COPD exacerbations, severity and mortality. Obeidat et al. reported that individuals with genes that tend to produce more SP-D have a protective effect against COPD.[21] In other words, individuals with higher serum SP-D levels tend to have lower compliance than individuals with lower serum SP-D levels. Lin, et al. reported that there was a significant increase in serum SP-D levels in the non-COPD group.[22] This may be supported by the function of SP-D in regulating surfactants.[21]

Similar to those studies, in our study it was found that an increase in SP-D levels was directly proportional to a decrease in the compliance level. That meant, there was a significant relationship between serum levels of SP-D with respiratory compliance.

In this study, the results were similar to the study of Tong et al. which stated that serum SP-D levels were significantly increased in severe COVID-19 patients compared to mild cases, whereas serum SP-D levels in the recovery period decreased dramatically compared to the acute phase.[10] Saito et al. reported that the serum levels of SP-D in cases of mild disease (non ARDS) compared to severe (ARDS) had a significant difference (P < 0.001). However, their research was carried out serially on days 3, 5 and 8; where the increase in the SP-D value on day 8 when compared to day 3 was 8.5 times higher and the increase in SP-D levels was also accompanied by worsened clinical condition.[9]

The results of the ROC curve analysis in the study showed that SP-D levels have a very strong diagnostic value for the severity of ARDS. Tong et al. reported that the area under the curve value of SP-D in predicting the severity of COVID-19 patients of 0.922 (95% CI 0.833–1,000, P < 0.001), with an optimal cutoff of 309.7 (sensitivity 88.9%, specificity 86.7%).[10]

SP-D is normally secreted in various parts of the body, but its concentration was significantly higher in ARDS patients (P = 0.001).[21] Type II alveolar cells and Club cells increase the release of SP-D in response to infectious agents to maintain airway immunity.[23] SP-D participates in pathogen elimination through agglutination, opsonization, and modulation of macrophage and dendritic cell function.[10] In a hyper-inflammatory state in SARS-CoV2 patients, an increase in SP-D which is positively correlated with an increase in interleukin IL-6, indicating a synergistic effect against pathogens.[23] The hyper-inflammatory state in ARDS is closely related to the role of SP-D in the modulation of the immune system, but it is still unclear whether SP-D has a protective or deleterious effect on the pathophysiology of ARDS.[10]

In this study, among patients with moderate ARDS, most showed low respiratory compliance, followed by normal compliance, and very low compliance. In patients with severe ARDS, most of the patients had very low respiratory compliance followed by low compliance, and there were no patients with normal compliance. This was similar to the research conducted by Panwar et al.[24] Patients with low compliance in Gattinoni's and Pesenti study also showed a predisposition to severe ARDS manifestations: hypoxemia, bilateral infiltrates, decreased respiratory system compliance, increased weight and lung recruit potential.[25] This study showed that there is a significant relationship between the level of respiratory compliance and the severity of ARDS with moderate strength.

Limitations of this study were small sample size leading to a possible biased results and no data of serum SP-D level in patients without ARDS (healthy people or COVID-19 patients with no ARDS) as baseline serum SP-D level of Indonesian are still not yet known. Therefore we could not compare the serum SP-D level of patients with and without ARDS. We suggest future study better be conducted with larger sample size and includes data of serum SP-D level in control group that consists of healthy people or COVID-19 patients without ARDS.


   Conclusion Top


There was significant correlation between serum level of SP-D with respiratory compliance and severity of ARDS. Higher serum SP-D levels were associated with lower respiratory compliance, ARDS severity, and may be utilized diagnostically to identify patients with severe ARDS.

Research quality and ethics statement

This study was approved by the Ethics Committee at our hospital (Approval # 0787/LOE/301.4.2/II/2022; Approval date February 5, 2022). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the STROBE guideline, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
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